biostudies-literatureYou TNIDDKe193208https://www.ebi.ac.uk/biostudies/studies/S-EPMC12288974biostudies-literatureUnknown10(14)More than 1 in 4 men will undergo surgery for inguinal hernia, which is commonly associated with fibrotic degeneration of the lower abdominal muscle (LAM) in the groin region. Utilizing a male mouse model expressing the human aromatase gene (Aromhum), previous studies showed that locally produced estradiol acting via estrogen receptor α in LAM fibroblasts leads to fibrosis, myofiber atrophy, and hernia development. Here, we found that upregulation of progesterone receptor (PGR) in a LAM fibroblast population mediates this estrogenic effect. A PGR-selective progesterone antagonist in Aromhum mice decreased LAM fibrosis and atrophy, preventing hernia formation and stopping progression of existing hernias. Addition of progesterone to estradiol treatment was essential for early-onset developmeJCI insightRole of progesterone action in inguinal hernia formation via skeletal muscle fibrosis and atrophy.PMC12288974T32DK007169R01DK139052R01DK121529Potluri TPiehl NZandigohar MYou TBaker EDai YLieber RLStulberg JJBulun SECoon V JSKafali MEscobar DJZhao HfalseRole of progesterone action in inguinal hernia formation via skeletal muscle fibrosis and atrophy.More than 1 in 4 men will undergo surgery for inguinal hernia, which is commonly associated with fibrotic degeneration of the lower abdominal muscle (LAM) in the groin region. Utilizing a male mouse model expressing the human aromatase gene (Aromhum), previous studies showed that locally produced estradiol acting via estrogen receptor α in LAM fibroblasts leads to fibrosis, myofiber atrophy, and hernia development. Here, we found that upregulation of progesterone receptor (PGR) in a LAM fibroblast population mediates this estrogenic effect. A PGR-selective progesterone antagonist in Aromhum mice decreased LAM fibrosis and atrophy, preventing hernia formation and stopping progression of existing hernias. Addition of progesterone to estradiol treatment was essential for early-onset developme2025-01-01T00:00:00Z2025 Jul2026-03-17T15:36:42.284Z2025-08-17T03:06:10.081ZS-EPMC122889744050461410.1172/jci.insight.193208